The Retroviral Diseases Section of the HIV and AIDS Malignancy Branch conducts translational clinical and laboratory research aimed at the development of novel therapies for HIV infection and AIDS- related malignancies. It also conducts laboratory research focused on an understanding of these diseases. During the past year, the group has investigated the role of conserved cysteines at positions 67 and 95 on the activity of HIV protease. We have found that glutathiolation of Cys 95 abolishes HIV-1 protease activity, while glutathiolation of Cys 67 can enhance activity. HIV virions with mutations of Cys 95 and Cys67 have been generated and we are studying the effects that these mutations have on the fitness of HIV under varying conditions. We are exploring the regulation of HIV-2 protease and have preliminary results showing that a methionine in position 95 of HIV-2 acts in a way similar to the cysteine in position 95 of HIV-1 in terms of regulating the protease activity. We are in the process of extending these observations to the proteases of other retroviruses and to HIV from patients on long-term protease inhibitor therapy who have a mutation at Cys 95. Also, we are attempting to design inhibitors of HIV protease that act through binding to these conserved cysteines. We are also exploring the possibility that certain protease inhibitors are metabolized under oxidative stress in monocytes. We have also continued the investigation of the combined activity of a newly discovered herpesvirus, called Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8), and HIV in the pathogenesis of Kaposi's sarcoma (KS). In particular, we are studying factors that induce the activation of this virus. We have evidence that hypoxia can activate latent KSHV to undergo lytic replication. We are also conducting several clinical trials to evaluate novel therapies for Kaposi's sarcoma with a focus on anti-angiogenesis approaches. We have recently obtained preliminary results indicating that the anti-angiogenesis agent thalidomide is active in a subset of patients with Kaposi's sarcoma. We are also studying IL-12 for possible activity in Kaposi's sarcoma and also the anti- herpes drug cidofovir and its effect on the expression of KSHV-related genes in KS. We have initiated a trial to investigate the mechanisms by which anti-HIV therapy may benefit KS. Study has been initiated to study the combination of IL-12 and a liposomal anthracycline in patients with advanced KS. We are also studying infusional chemotherapy and IL-12 as therapy for AIDS-associated lymphoma. In regard to anti-HIV therapy, a clinical trial is under way to study two HIV envelope peptide vaccines in HIV-infected patients in combination with highly active antiretroviral therapy. Preliminary results indicate that the vaccine can boost proliferative T cell responses against HIV in a majority of patients. A study is planed to investigate a vaccinia-virus based HIV vaccine. 100% AIDS related